Oral HIV-1 transmission is well documented in children who become infected postnatally through breast milk. In contrast, epidemiological surveys have yielded conflicting data regarding oral HIV-1 transmission among adults, even though case reports have described infection in adults whose only risk was oral/genital contact. In earlier work, we exposed rhesus macaques of various ages to cell-free SIV. In neonates, viremia and AIDS developed after non-traumatic oral exposure to several strains, including chimeric SHIV containing HIV-1 env. In adult macaques, well controlled, non-traumatic experimental oral exposure to uncloned as well as molecularly cloned SIV resulted in systemic infection. Many questions regarding oral lentiviral infection remain unanswered, e.g., the tropism of the virus strains that can traverse the upper gastro-intestinal mucosal surfaces, the site(s) of viral entry, and the potential role of inflammation in the oral cavity in facilitating virus transmission. The Specific Aims of this proposal are to: 1. Test the hypothesis that macrophage (M)-tropic strains are transmitted preferentially after oral inoculation. 2. Test whether neonates are more susceptible to systemic infection after oral SIV inoculation than adults. 3. Test the hypothesis that the presence of inflammation in the oral cavity facilitates virus transmission. 4. Test whether the eruption of teeth (and its accompanying gingival inflammation) increases the susceptibility of infant macaques to orally administered SIV. 5. Determine site(s) of virus entry and initial target cells after oral inoculation. We will perform serial sacrifice experiments to identify the site(s) of SIV passage across the mucosa and the initial target cells. This work is significant because it will shed light on key aspects of the mechanisms involved in oral virus transmission in adult and neonatal primates, including identification of important cofactors in oral virus transmission. The data generated will help in formulating strategies to decrease the risks of oral HIV-1 transmission, including late virus transmission during breast feeding. transport and the roles of TC10 in cellular growth.